There is an urgent need for a vaginal product that would not only protect against AIDS and other sexually transmitted infections, but would also prevent conception. We propose to develop such a product by combining the microbicide Carraguard, which is the sulfated polysaccharide, carrageenan, with the synthetic progestin, levonorgestrel (LNG). Laboratory studies have shown that Carraguard is highly effective in blocking HIV in vitro and in mice has effectively protected against vaginal and rectal infection by herpes simplex virus-2 and has blocked infection by Neisseria gonorrhoeae. Carraguard has also prevented human papillomavirus infection in human xenografts. Its extensive history of safety and stability as a food additive and a pharmaceutical excipient and its physcial properties, allowing Carraguard to act as a vehicle as well as a microbicide, make this agent an ideal candidate for use in a microbicide/contraceptive combination. The progestogen component, LNG, used by women worldwide for 30 years, has a proven record of contraceptive efficacy and safety. Another important feature of LNG is its long half-life, which may allow for occasional use of the combination gel "on demand" before intercourse. The proposed project will include in vitro and animal studies to evaluate the compatibility of the two agents in the CARRA/LNG formulation, regarding hormone release, stability of components and the formulation, and microbicidal and contraceptive efficacy. The proposed clinical studies will establish proof of concept of CARRA/LNG, vaginal retention profile, the feasibility of vaginal administration, the pharmacokinetic profile, safety and acceptability. The clinical studies will target three modes of contraception: 1) contraception on demand, delivering two high doses of CARRA/LNG during the follicular phase to delay the LH peak and to alter cervical mucus thus inhibiting sperm penetration; 2) induction of local effects (e.g., alteration of cervical mucus and transformation of the endometrium) using daily-low dose LNG in the combined product, which would prevent sperm penetration and implantation; and 3) induction of a systemic effect with daily use of high-dose LNG delivered via Carraguard gel that would decrease LH and FSH and suppress ovulation.